Docetaxel is an antineoplastic agent belonging to the taxoid family being marketed by Sanofi-Aventis under trade name TAXOTERE® (injection concentrate of docetaxel and polysorbate 80). It is prepared by semisynthesis beginning with a precursor extracted from the renewable needle biomass of yew plants. The chemical name for docetaxel is (2R,3S)—N-carboxy-3-phenylisoserine, N-tert-butyl ester, 13-ester with 5beta-20-epoxy-1,2α,4,7β,10β,13α-hexahydroxytax-11-en-9-one 4-acetate 2-benzoate, trihydrate. Docetaxel has the following structural formula:
Docetaxel, as currently marketed by Sanofi-Aventis, is a white to almost-white powder with an empirical formula of C43H53NO14.3H2O, and a molecular weight of 861.9. It is highly lipophilic and practically insoluble in water. TAXOTERE® (docetaxel) Injection Concentrate is a clear yellow to brownish-yellow viscous solution. TAXOTERE® is sterile, non-pyrogenic, and is available in single-dose vials containing 20 mg (0.5 ml) or 80 mg (2 ml) docetaxel (on an anhydrous basis). Each ml contains 40 mg docetaxel (on an anhydrous basis) and 1040 mg polysorbate 80. For purposes of this specification, reference to an amount of “docetaxel” without reference to the specific form (i.e., hydrate, salt, etc.) will mean the stated amount of the free, anhydrous, non-solvated moiety of the drug in question unless the context clearly requires otherwise, notwithstanding the actual form of the compound then under discussion. Thus, for example, reference to 80.7 mg of docetaxel without reference to the form of the drug, means that amount of the actual drug form used which corresponds to the same number of moles of the docetaxel moiety as 80.7 mg of free, unsolvated, anhydrous docetaxel. If free docetaxel trihydrate were to be used, this would mean 86.1 mg of free docetaxel trihydrate. Similar calculations for salts and solvates will be apparent to those of ordinary skill in the art.
TAXOTERE® Injection Concentrate requires dilution prior to use. A sterile, non-pyrogenic, single-dose diluent is supplied for that purpose. The diluent for TAXOTERE® contains 13% ethanol in water for injection, and is supplied in vials. The preparation of the dilution is in two phases. The concentrate (which is stored between 2-25° C. (36 and 77° F.)) is allowed to come to room temperature, if not already, along with any necessary diluent (13% ethanol in water for injection for the commercially available material) by letting them stand under room temperature conditions for about 5 minutes. Diluent is aseptically withdrawn from its vial (approximately 1.8 ml for TAXOTERE®20 mg and approximately 7.1 ml for TAXOTERE® 80 mg) into a syringe by partially inverting the vial, and transferring it to the appropriate vial of TAXOTERE® Injection Concentrate. If the procedure is followed as described, an initial diluted solution of 10 mg docetaxel/ml will result. This initial dilution is mixed by repeated inversions for at least 45 seconds to assure full mixture of the concentrate and diluent. The vial should not be shaken. The resulting solution (10 mg docetaxel/ml) should be clear; however, there may be some foam on top of the solution due to the polysorbate 80. The initial diluted solution may be used immediately or stored either in the refrigerator or at room temperature for a maximum of 8 hours.
The current TAXOTERE® label indicates that the required amount of docetaxel is then aseptically withdrawn from the initial 10 mg docetaxel/ml solution with a calibrated syringe and injected into a 250 ml infusion bag or bottle of either 0.9% Sodium Chloride solution or 5% Dextrose solution to produce a final concentration of 0.3 to 0.74 mg/ml. If a dose greater than 200 mg of TAXOTERE® is required, a larger volume of the infusion vehicle is used so that a concentration of 0.74 mg/ml docetaxel is not exceeded. (It has been found that if this maximum is exceeded in the final infusion concentration, the TAXOTERE® precipitates out of the formulation having the polysorbate as the solubilizer.) The infusion is then thoroughly mixed by manual rotation. The final TAXOTERE® dilution for infusion should be administered intravenously as a 1-hour infusion under ambient room temperature and lighting conditions.
TAXOTERE® infusion solution, if stored between 2 and 25° C. (36 and 77° F.) is stable for 4 hours. Fully prepared TAXOTERE® infusion solution (in either 0.9% Sodium Chloride solution or 5% Dextrose solution) should be used within 4 hours (including the 1 hour intravenous administration).
The present marketed docetaxel (in TAXOTERE®) is dissolved in 100% (w/v) polysorbate 80 (Tween-80) which results in severe side effects. Severe hypersensitivity reactions characterized by generalized rash/erythema, hypotension and/or bronchospasm, or very rarely fatal anaphylaxis, have been reported in patients in spite of receiving the recommended 3-day dexamethasone premedication. Hypersensitivity reactions require immediate discontinuation of the TAXOTERE® infusion and administration of appropriate therapy. All the hypersensitive reactions mentioned above are primarily caused by and due to the presence of polysorbate 80 in the formulation. In order to reduce the side effects induced by polysorbate 80, all patients are treated with dexamethasone for three days prior to therapy. Dexamethasone is a steroid that suppresses the immune response in patients. Cancer patients under chemotherapy generally have a low level of immunity due to the destruction of healthy cells by the chemotherapeutic agents. Treatment with steroids will further compromise the patient's immunity and patients will be susceptible to bacterial and fungal attacks. Due to these side effects, most of the patients drop out of docetaxel therapy by the end of 2nd or 3rd cycle or skip a dose or continue further therapy at reduced dose. The recommended therapy is 6 cycles of docetaxel given once every three weeks. Thus, therapeutic activity and the maximum tolerated dose (MTD) of docetaxel are compromised due to the presence of polysorbate 80 in the formulation. Other solubilizing agents such as Cremophor EL (used in connection with the marketed paclitaxel product Taxol®) having similar allergic reactions (requiring pre-medication with steroids and antihistamines) should also be avoided.
The inventor's prior efforts at formulations of this type are seen in U.S. Ser. No. 12/214,506, filed Jun. 19, 2008, published as US 2008/0319048 on Dec. 25, 2008 and as WO/2009/002425 on Dec. 31, 2008. Those efforts included the use of a select number of solvents inclusive of glycofurol to prepare an initial concentrate, and a select number of diluent materials inclusive of TPGS, additional glycofurol, and optionally relatively large amounts of antioxidants for diluting the initial concentrate to an intermediate concentrate for use within a relatively short time to prepare the infusion for administration. Notwithstanding the advantages of those formulations, improvements thereover were still necessary and such improvements have resulted in the present invention.